Researchers Shed Light on Link Between IGF-1 and Potential Benefits in Rett Syndrome

Treatment with insulin-like growth factor 1 (IGF-1) eases symptoms of Rett syndrome by suppressing the activity of FXYD1 — a molecule found in higher-than-normal levels in Rett patients — according to a study in a mouse model of the disorder.

Besides supporting the previously reported potential benefits of IGF-1 treatment in Rett patients, these findings may help identify new therapeutic targets and develop new treatments for this disease.

The study, “Insulin-Like Growth Factor-1 Down-Regulates the Phosphorylation of FXYD1 and Rescues Behavioral Deficits in a Mouse Model of Rett Syndrome,” was published in the journal Frontiers in Neuroscience.

Rett syndrome is a rare neurodevelopmental disorder caused mainly by mutations in the MECP2 gene, which contains the instructions to produce the MeCP2 protein. MeCP2 regulates the activity of other genes, and is involved in the growth, function, and communication of nerve cells.

IGF-1 is a naturally occurring growth factor in the brain, required for its normal development and response to injury and disease. In the brain, IGF-1 is broken down into a small protein fragment with similar functions, called glypromate.

Abnormally low levels of IGF-1 have been found in the central nervous system (brain and spinal cord) of Rett patients. As such, restoring the levels of IGF-1 and glypromate may help repair brain deficits in this patient population.

Neuren Pharmaceuticals (and Acadia Pharmaceuticals in North America) are developing a potential Rett treatment called trofinetide, which is a modified, more efficient and long-lasting form of glypromate. It is intended to reduce inflammation and promotes neuroprotective effects to ease Rett symptoms.

Notably, a Phase 3 clinical trial, named LAVENDER (NCT04181723), is currently recruiting girls and young women (ages 5 to 20) with Rett syndrome to evaluate the safety and effectiveness of trofinetide.

FXYD1 is a small membrane protein that regulates the activity of an enzyme called Na, K-ATPase, which is involved in restoring ion balance after nerve cell excitation (or activation).

Prior studies showed that reducing FXYD1 levels eases disease-associated mechanisms in the brain of mice engineered to mimic symptoms of Rett, suggesting the potential role of FXYD1, a target of MECP2, in the disease.

Now, researchers in China used a mouse model of Rett to better understand the mechanisms behind IGF-1 treatment’s effects.

They found that IGF-1 treatment improved or nearly normalized behaviors (hoarding of food), motor coordination, and cognitive function in Rett mice.

Also, IGF-1 lowered the excessive levels of FXYD1 messenger RNA (mRNA) — derived from DNA in FXYD1 protein production — in the brain of these mice. However, no significant changes in FXYD1 protein levels were found between treated and non-treated mice.

Next, the researchers analyzed whether IGF-1 could influence the localization and function of FXYD1, which is regulated by a chemical modification called phosphorylation. Phosphorylated FXYD1 (p-FXYD1) is more prone to move to the membrane, where it exerts its function.

Data showed that brain levels of p-FXYD1 were significantly higher in the Rett model, compared with those of healthy mice, and that IGF-1 treatment partially normalized these levels. The team also found that IGF-1’s effects on FXYD1 phosphorylation were dependent on a signaling pathway called PI3K-AKT-mTOR.

These findings suggest that IGF-1 treatment suppresses FXYD1 phosphorylation and consequently its membrane localization and function.

“[W]e found, for the first time, that IGF-1 can relieve the symptoms of RTT by [lowering] the phosphorylation level of FXYD1, which provides a new therapeutic mechanism for a large class of neurodevelopmental disorders,” the researchers wrote.

However, further studies are required to better understand the molecular processes driving IGF-1 therapeutic effects in Rett syndrome, they added.